Table 2 TPP-1 profiles for treatment of children or adults infected with malaria

Parameter to be demonstrated for the combination in clinical evaluation

Minimum essential

Ideal

Rate of onset of action

At least one component acts immediately; fever clearance at 24 h

Both components act immediately; fever clearance at 24 h

Proportional reduction in parasite load

Capable of achieving >12 log10 unit reduction in asexual blood-stage load; >95% patients free from parasites with from one to three doses

>12 log10 unit reduction in asexual blood-stage load in >95% patients with a single dose

Parasite-free (day 7), including patients from areas with known drug-resistance to current first-line medications

100%

100%

Clinical efficacy (ACPR at day 28 or later; per protocol)

>95% PCR-corrected, in a per-protocol population; on day 28; non-inferior to standard of care

>95% PCR-corrected, in a per-protocol population, on days 42–63; non-inferior to standard of care

Transmission blocking

Not required per se, but must not display detrimental drug–drug interactions with low-dose (0.25 mg/kg) primaquine

Combination should prevent clinical transmission, with no oocysts found in mosquitoes used in direct feeding or ex vivo experiments 15 days post treatment dose, without the need for low-dose primaquine

Relapse prevention: prevents the relapse of P. vivax, and by inference P. ovale.

Not required per se, but must not display drug–drug interactions with a relapse-preventing dose of 8-aminoquinoline

Confirmation in clinical studies (6 months in South America, Ethiopia and SE Asia, and the Pacific Ocean, potentially 24 months in India, Pakistan and Afghanistan)

Bioavailability/food effect

Predicted to be >30% for each molecule/ less than threefold (likely will be known by this stage)

Predicted to be >50% for each molecule/none (likely will be known at this stage

Drug-drug interactions

No unmanageable risk in terms of solid state or PK interactions

No risks in terms of solid state or PK interactions

Dosing regimen

Oral, two or three doses

Oral, once

Safety and tolerability

Few and manageable drug-related SAEs (serious adverse events), or adverse events leading to exclusion from study in phase III

No drug related SAEs; minimal drug-related AEs;
no enhanced risk, no risk of hemolysis in subjects with reduced G6PD activity

Pregnancy

Not contra-indicated in second or third trimester

Not contra-indicated in second or third trimester, no suggestion of embryo-fetal toxicity in first trimester in preclinical species

Formulations

Co-formulated tablets or equivalent, with taste-masking (if needed) for pediatrics